Cutaneous ulcers afflict approximately 4.5 million patients in the United States each year and it is estimated that 15% of older adults in the United States suffer from chronic, hard-to-heal skin wounds. Many of these wounds fail to heal, often resulting in severe complications including amputations and life-threatening infections. The healing of these wounds is often impaired by hypoxia, so strategies to enhance vascularization and simultaneously stimulate multiple repair processes have the potential to significantly improve the treatment and healing of chronic wounds. Stratatech Corporation is developing a portfolio of engineered skin tissue products to improve the management and healing of chronic skin wounds. While administration of individual angiogenic factors may stimulate some aspects of angiogenesis, the simultaneous expression of multiple factors is required to promote morphologically and functionally normal vessels. This Phase I proposal is designed to test the hypothesis that keratinocytes can be engineered to coordinately express elevated levels of multiple therapeutic factors. This will be accomplished by stably introducing a master regulator of hypoxia-induced wound healing responses into a proprietary keratinocyte cell source using non-viral vectors and characterizing the expression and secretion of biologically-active angiogenic factors. If successful, the proposed research will ultimately lead to the development and commercialization of improved treatments to promote the healing of chronic wounds and other severe skin defects.